Project Summary Each day we make hundreds of reward-seeking decisions. These choices are influenced by expectations about future rewards, which can be elicited by environmental reward-predictive cues and knowledge about the consequences of our actions. These cognitive processes allow us to anticipate future events, and make adaptive choices based on these predictions. This process can, however, become dysfunctional, leading to psychological symptoms that underlie addiction and other disorders of behavioral control. For example, the maladaptive drug- seeking decisions that characterize addiction may arise from an impairment in the ability to retrieve and use of specific details (including both positive and negative features) about anticipated events (e.g., drug consumption) to guide choices. Expectation-guided behaviors are thought to be mediated by complex networks of interconnected brain regions. Evidence suggests that two major nodes in this network are the basolateral amygdala (BLA) and orbitofrontal cortex (OFC), both of which have been implicated in expectation-guided decision making. These regions share dense excitatory connections, and there is evidence that the BLA may contribute to associative encoding in the OFC. Understanding of this circuit has however, recently been complicated by findings that the medial (mOFC) and lateral OFC (lOFC) are anatomically and functionally distinct. The exact type of information conveyed from the BLA to the OFC, and whether this is distinct based on OFC subregion, is an important unanswered question. Using rodent models, the first objective of this proposal is to examine how BLA projections to the medial and lateral OFC are recruited by situations in which reward expectations are generated by reward-predictive cues or known action-reward relationships. Given preliminary findings suggesting BLA mu-opioid receptor activation is necessary for expectation-guided behavior, this aim will also test the hypothesis that this receptor regulates the excitability of BLA projection neurons. Preliminary data indicate a causal role of BLA projections to the lOFC in behaviors mediated by cue-provided reward expectations. The second objective will evaluate the function of BLA projections to the mOFC in reward expectation-guided behavior. These aims will provide me with a breadth of training in immunohistochemistry, microscopy for ex vivo tissue analysis and automated quantification, in vivo glutamate biosensing, and optogenetic methods. The findings from this proposal will expose new information on the neural circuitry of expectation-guided decisions and will contribute to the understanding and development of potential new treatments for drug addiction.